Anti-inflammatory agents

ABSTRACT

This invention is directed to the use of certain arylacetylene compounds, principally as anti-inflammatory agents but also as anti-pyretic agents and as analgesic agents.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to methods employing, and compositionscomprising, arylacetylene compounds of the following formula: ##SPC1##

Wherein q represents 0, 1, or 2; each R¹ independently representschloro, fluoro, methyl, or methoxy; m represents 0 or 1; and R²represents

1. phenyl;

2. substituted phenyl of the formula ##SPC2##

Wherein each R³ independently represents chloro, fluoro, or methyl, andn represents 1 or 2; or

3. where q = 1 and at least one R¹ = chloro, fluoro, or methyl,

A. n-butyl or

B. cycloalkyl of C₅ -C₇. The bracket unit "{" is employed to indicatethat the R² -(O)_(m-) substituent is attached to the phenyl ring at aposition either meta or para to the acetylene moiety.

The above described compounds exhibit antiinflammatory activity, as wellas analgesic activity and anti-pyretic activity. Certain of thecompounds are novel and are claimed per se.

DETAILED DESCRIPTION OF THE INVENTION

The compounds to be employed in accordance with the present inventionare prepared by any of several synthetic routes. The most preferredroute is as ##SPC3##

In this route, an acetophenone is halogenated, typically brominated orchlorinated, to obtain an α-halostyrene, which on dehydrohalogenationyields the desired compound. Although halogenation of a carbonylcompound is generally carried out with phosphorous pentabromide orpentachloride, equivalent results have been obtained in the presentsynthesis by using a mixture of the phosphorous pentahalide with thecorresponding phosphorous oxyhalide. The amounts of these agents are notcritical; conveniently, an excess is employed, the phosphorous oxyhalideserving as a reaction medium. However, other inert reaction media, suchas benzene, toluene, etc., can be used. The reaction goes best atelevated temperatures, such as 40°-200° C. Separation and, if desired,purification, are carried out in conventional procedures.

In the second step of this reaction route, the resulting α-halostyreneis dehydrohalogenated. The identity of reagent is not critical; strongbases such as sodium amide, lithium amide, or potassium amide insolution in liquid ammonia, or potassium tertiary butoxide in dimethylsulfoxide, give good results. The dehydrohalogenation is preferablyconducted at temperatures of -30° to 0° C. Separation and purification,if desired, are carried out in conventional procedures.

In an alternate synthetic route, an arylstyrene is halogenated (Br, Cl,or I) and subsequently dehydrohalogenated: ##STR1## The halogenationreaction is generally run at low temperatures, such as -20° to 20° C.,using as reaction medium an inert organic solvent such as chloroform,methylene chloride, diethyl ether, benzene, or toluene. Separation andpurification are carried out in conventional procedures.

The subsequent dehydrohalogenation reaction is carried out as discussedabove in the first synthetic route.

The following examples illustrate the synthesis of the compounds to beemployed in the present invention.

EXAMPLE 1: (4-(2-FLUOROPHENYL)PHENYL)ACETYLENE

A mixture of 86.5 g. of 4'-(2-fluorophenyl)-acetophenone, 94 g. ofphosphorus pentachloride, and 225 ml. of phosphorus oxychloride washeated at 60° C. for 20 hours. After cooling, the mixture was evaporatedin vacuo and the residue, containing 4-(2-fluorophenyl)-α-chlorostyrene,was azeotroped four times with dry benzene. The residue was dissolved intetrahydrofuran and added dropwise to a solution of sodium amideprepared by addition of 46 g. of metallic sodium to 1500 ml. of liquidammonia containing a few mg. of ferric chloride. After 750 ml. of drydiethyl ether were added, the reaction was stirred overnight. Thereaction was treated with 150 ml. of saturated ammonium chloridesolution, then with 100 ml. water and poured onto ice. The organic layerwas separated and the aqueous layer was extracted with diethyl ether andethyl acetate. The combined organic extracts were washed with water, 5%hydrochloric acid, and water, and dried over sodium sulfate. Evaporationof the solvents in vacuo left a liquid residue which was fractionallydistilled to yield 30.7 g. of (4-(2-fluorophenyl)phenyl)acetylene, b.p.94°-97° C./0.2 mm., n_(D) ²⁴ = 1.6185. On standing, the compoundsolidified, m.p. 28.5°-31.0° C.

Analysis, Calc. for C₁₄ H₉ F: C, 85.69; H, 4.62; F, 9.68,

Found: C, 85.46; H, 4.45; F, 9.39.

EXAMPLES 2-24:

The following compounds were prepared from the indicated ketoneaccording to the method of Example 1, using appropriate amounts ofphosphorus pentachloride, phosphorus oxychloride, sodium amide, andammonia:

4-Biphenylylacetylene, m.p. 76°-81° C., from 4'-phenylacetophenone.

Analysis, Calc. for C₁₄ H₁₀ :C, 94,34; H, 5.66,

Found: C, 94.16; H, 5.87.

(2-Methyl-4-phenoxyphenyl)acetylene, b.p. 110°-112° C./0.35 mm., n_(D)²⁵ = 1.5994, from 2'-methyl-4'-phenoxyacetophenone

Analysis, Calc. for C₁₅ H₁₂ O: C, 86.51; H, 5.81; O, 7.68,

Found: C, 86.24; H, 6.02; O, 7.63.

(3-Methyl-4-phenoxyphenyl)acetylene, b.p. 103°-105° C./0.1 mm., n_(D) ²³= 1.5949, from 3'-methyl-4'-phenoxyacetophenone.

Analysis, Calc. for C₁₅ H₁₂ O: C, 86,51; H, 5.81; O, 7.68;

Found: C, 86.42; H, 5.81; 0, 7.39.

(4-Phenoxyphenyl)acetylene, b.p. 105°-111° C/0.3 mm., n_(D) ²⁵ = 1.6045,from 4'-phenoxyacetophenone.

Analysis, Calc. for C₁₄ H₁₀ 0 = C, 86.57; H, 5.19; O, 8.24,

Found: C, 86.31; H, 4.97; O, 8.24.

(3-Methoxy-4-phenylphenyl)acetylene, b.p. 133°-134° C./0.2 mm., from3'-methoxy-4'-phenylacetophenone.

Analysis, Calc. for C₁₅ H₁₂ O: C, 86.51; H, 5,81,

Found: C, 86.26; H, 5.94.

(3-Phenoxyphenyl)acetylene, b.p. 90° C./0.2 mm., n_(D) ²³ = 1.5987, from3'-phenoxyacetophenone.

Analysis, Calc. for C₁₄ H₁₀ O: C, 86.57; H, 5.19; O, 8.24,

Found: C, 86.30; H, 5.18; O, 8.04.

(3,5-Dimethyl-4-phenoxyphenyl)acetylene, b.p. 145°-146° C. /0.1 mm.,n_(D) ²⁵ =1.5882, from 3',5'-dimethyl-4'-phenoxyacetophenone.

Analysis, Calc. for C₁₆ H₁₄ O: C, 86.45; H, 6.35; O, 7.20,

Found: C, 86.20; H, 6.37; O, 7.17.

3-Biphenylylacetylene, b.p. 98°-100° C./0.4 mm., n_(D) ²⁵ = 1.6300, from3'-phenylacetophenone.

Analysis, Calc. for C₁₄ H₁₀ : C, 94.34; H, 5.66,

Found: C, 94.53; H, 5.43.

(3-Chloro-4-cyclohexylphenyl)acetylene, b.p. 108°-112° C./0.4 mm., n_(D)²⁵ = 1.5698, from 3'-chloro-4'-cyclohexylacetophenone.

Analysis, Calc. for C₁₄ H₁₅ Cl: C, 76.88; H, 6.91,

Found: C, 76.73; H, 6,84.

(4-(2-Chlorophenyl)phenyl)acetylene, b.p. 101°-106° C./0.1 mm., from4'-(2-chlorophenyl)acetophenone.

Analysis, Calc. for C₁₄ H₉ Cl: C, 79.06; H, 4.27; Cl, 16.67,

Found: C, 76.92; H, 4.55; Cl, 16.41.

(2-Methoxy-4-phenylphenyl)acetylene, m.p. 53°-55° C., from2'-methoxy-4'-phenylacetophenone.

Analysis, Calc. for C₁₅ H₁₂ O: C, 86.51; H, 5.81; O, 7.68.

Found: C, 86.43; H, 6.07; O, 7.48.

(4-(3-Fluorophenyl)phenyl)acetylene, b.p. 87°-89° C.0.07 mm., n_(D) ²⁵ =1.6229, from 4'-(3-fluorophenyl)acetophenone.

Analysis, Calc. for C₁₄ H₉ F: C, 85.69; H, 4.62; F, 9.68,

Found: C, 85.48; H, 4.87; F, 9.40.

(4-(2,4-Difluorophenyl)phenyl)acetylene, b.p. 95°-101° C./0.1 mm., from4'-(2,4-difluorophenyl)acetophenone.

Analysis, Calc. for C₁₄ H₈ F₂ : C, 78.50; H, 3.76,

Found: C, 78.48; H, 4.01. (4-(2,5-Difluorophenyl)phenyl)acetylene, b.p.100°-102° C./0.2 mm., from 4'-(2.5-difluorophenyl)acetophenone.

Analysis, Calc. for C₁₄ H₈ F₂ : C, 78.50; H, 3.76,

Found: C, 78.71; H, 4.03.

(2-Methyl-4-n-butoxyphenyl)acetylene, b.p. 100° C./0.4 mm., from4'-n-butoxy-2'-methylacetophenone.

Analysis, Calc. for C₁₃ H₁₆ O: C, 82.94; H, 8.57; O, 8.50,

Found: C, 83.22; H, 8.70; O, 8.31.

(4-(2,6-Difluorophenyl)phenyl)acetylene, m.p. 81°-83° C., from4'-(2,6-difluorophenyl)acetophenone.

Analysis, Calc. for C₁₄ H₈ F₂ : C, 78.50; H, 3.76; F, 17.74,

Found: C, 78.27; H, 3.99; F, 17.98.

(4-(o-tolyl)phenyl)acetylene, m.p. 29°-30° C., from4'-(o-tolyl)acetophenone.

Analysis, Calc. for C₁₅ H₁₂ : C, 93.71; H, 6.29,

Found: C, 93.50; H, 6.38.

(3-Methyl-4-phenylphenyl)acetylene, m.p. 57°-59° C., from3'-methyl-4'-phenylacetophenone.

Analysis, Calc. for C₁₅ H₁₂ ; C, 93.71; H, 6.29,

Found: C, 91.63; H, 6.24.

(3-Chloro-4-phenylphenyl)acetylene, b.p. 97°-100° C./0.09 mm., from 3'-chloro-4'-phenylacetophenone

Analysis, Calc. for C₁₄ H₉ Cl: C, 79.06; H, 4.27,

Found: C, 78.81; H, 4.07.

(3-Fluoro-4-phenylphenyl)acetylene, b.p. 103° C./0.6 mm., from3'-fluoro-4'-phenylacetophenone.

analysis, Calc. for C₁₄ H₉ F: C, 85.69; H, 4.62; F, 9.68,

Found: C, 85.48; H, 4.66; F, 9.42.

(4-Fluoro-3-(2-fluorophenyl)phenyl)acetylene, b.p. 112°-120° C./0.05mm., from 4'-fluoro-3'-(2-fluorophenyl)acetophenone.

Analysis, Calc. for C₁₄ H₈ F₂ : C, 78.50; H, 3.76; F, 17.74,

Found: C, 77.0; H, 3,84; F, 17.66

(4-(2-Fluorophenoxy)phenyl)acetylene, b.p. 110°-114° C./0.3 mm., n_(D)²⁵ = 1.5860, from 4'-(2-fluorophenoxy)acetophenone.

Analysis, Calc. for C₁₄ H₉ FO: C, 79.23; H, 4.27,

Found: C, 79.00; H, 4.41.

(3-(2-Fluorophenoxy)phenyl)acetylene, b.p. 93°-96° C./0.2 mm., from3'-(2-fluorophenoxy)acetophenone.

Analysis, Calc. for C₁₄ H₉ FO: C, 79.23; H, 4.27; F, 8.95,

Found: C, 78.95; H, 4.30; F, 8.71.

EXAMPLE 25: 4-BIPHENYLYLACETYLENE

A solution of 19.2 g. of bromine in carbon tetrachloride was addeddropwise to a cooled, stirred carbon tetrachlorid e solution of 21.3 g.of 4-phenylstyrene. Cooling was maintained during the bromine additionso that the reaction temperature did not exceed 5° C. The reactionmixture was allowed to warm to room temperature and was then stirredovernight and poured into ice water. The carbon tetrachloride layer wasseparated and the aqueous layer was extracted with additional carbontetrachloride. The combined carbon tetrachloride solutions were washedwith water, dried over sodium sulfate, and evaporated to dryness invacuo to yield crude 4-(1,2-dibromoethyl)biphenyl, m.p., 123°-126° C.

Analysis, Calc. for C₁₄ H₁₂ Br₂ : C, 49.45; H, 3.56; Br, 46.99,

Found: C, 49.34; H, 3,73; Br, 47.07.

A solution of 39 g. of the 4-(1,2-dibromoethyl)biphenyl in 400 ml. of a1:1 mixture (by volume) of dimethyl sulfoxide and tert-butanol was addedrapidly, with cooling (10°-15° C.) and stirring, to a solution of 26 g.of potassium-tert-butoxide in 400 ml. of a 1:1 mixture (by volume) ofdimethyl sulfoxide and tert-butanol. After stirring for 20 minutes, thereaction mixture was poured into ice water. The aqueous mixture wasextracted with diethyl ether. The ether extract was washed with water,5% sodium bicarbonate, and water, and dried over sodium sulfate. Theether was evaporated in vacuo, and the residue crystallized from ethanoland water to yield 18.5 g. of crude 4-biphenylylacetylene, m.p. 79-81°C. Two recrystallizations from hexane gave pure 4-biphenylylacetylene,m.p. 82.85° C.

Analysis, Calc. for C₁₄ H₁₀ : C, 94.34; H, 5.66,

Found: C, 94.27; H, 5.68.

Preferred compounds are those wherein m = O and R² = phenyl, substitutedphenyl as defined or cycloalkyl as defined and the R² group is at thepara position. Yet more preferred compounds are those of thelast-described group bearing one substituent ortho to the phenyl-phenylor cycloalkyl-phenyl bond. Preferred specific compounds are4-biphenylylacetylene; (4-(2-fluorophenyl)phenyl)acetylene;(4-(2,5-difluorophenyl)phenyl)acetylene;4-(2,4-difluorophenyl)phenyl)acetylene;(3-chloro-4-cyclohexylphenyl)acetylene; (4-(o-tolyl)phenyl)acetylene;(3-chloro-4-phenylphenyl)acetylene; (3-fluoro-4-phenylphenyl)acetylene;and (3-methyl-4-phenylphenyl)acetylene. Compounds which are claimed ascompounds are (4-(2-fluorophenyl)phenyl)acetylene;(3-chloro-4-phenylphenyl)acetylene; (3-methyl-4-phenylphenyl)acetylene;(3-fluoro-4-phenylphenyl)acetylene;(4-(2,4-difluorophenyl)phenyl)acetylene; and(4-(2,5-difluorophenyl)phenyl)acetylene.

As set forth above, the compounds to be employed in accordance with thepresent invention exhibit anti-inflammatory, analgesic, and antipyreticactivity. The present invention is therefore directed to methodsemploying the compounds for the treatment of inflammation, fever, andpain. In the practice of these methods, one or more of the compounds isadministered to a warm blooded animal needing such treatment, therebyalleviating symptoms of inflammation, fever, and pain. The circumstancescausing these various symptoms are legion. The compounds to be employedin accordance with the present invention are especially suited to beused in the management of rheumatoid arthritis. However, those skilledin the art will recognize that the present methods will also beeffective in the treatment of numerous other conditions which produceinflammation, fever, or pain, such as rheumatoid spondylitis,degenerative joint disease, and minor conditions of inflammation, pain,or fever of unspecified origin.

The amount of the compound or compounds employed is not critical, solong as an effective, anti-inflammatory, anti-pyretic, or analgesicamount is used. In general, anti-inflammatory activity is exhibited atdoses of from 0.01 to 50 or more mg./kg. of animal body weight.Anti-pyretic activity is typically exhibited at doses of from 10 to 100mg./kg. of animal body weight, while analgesic activity is generallyexhibited at doses of from 1 to 100 mg./kg. of animal body weight. Thedose may be repeated where continued thereapy is appropriate.

In carrying out the methods of the present invention, it is generallypreferred to employ a composition comprising the active agent and one ormore adjuvants suited to the particular route of administration.Compositions for oral administration may be either solid, e.g.,capsules, tablets, pills, powders, etc., or liquid, e.g., emulsions,solutions, suspensions, syrups, elixirs, etc. Inasmuch as some of thecompounds to be employed as active agent are liquids, soft elasticgelatin capsules are often suitably employed for oral administration. Inany of these various forms, the active agent can be combined withconventional adjuvants. In the case of solid formulations, suitableadjuvants include inert substances such as sucrose, lactose, and starch.In the case of liquid formulations, suitable adjuvants include water,mineral oil, etc. Either solid or liquid formulation can includelubricating agents, wetting agents, emulsifying and suspending agents,preserving agents, sweetening agents, flavoring agents, or perfumingagents.

In the instance of rectal administration, the compounds are suitablyformulated as a suppository, such as by combination with an excipientsuch as cocoa butter. A hardening agent may appropriately be added toadjust the melting point of the suppository.

In the instance of parenteral administration, the compounds of thepresent invention are formulated in a suitable sterile, injectableliquid.

Formulations suitable for topical administration include lotions,ointments, creams, sprays, etc. Conventional adjuvants are employed.

In general, oral administration is preferred. Accordingly, a preferredformulation is a pharmaceutical preparation in dosage unit form adaptedfor administration to obtain an anti-inflammatory, antipyretic, oranalgesic effect, composing, per dosage unit, an effective non-toxicamount within the range from about 1 to about 1000 milligrams of one ormore of the compounds to be employed in accordance with the presentinvention. In many applications, the above preparation may suitablycontain only a lesser amount of active agent, such as from about 5 toabout 500 milligrams, or an even lesser amount of active agent, such asfrom about 25 to about 125 milligrams.

The following examples illustrate the methods and formulations of thepresent invention. Example 26:

(4-(2-Fluorophenyl)phenyl)acetylene is added to microcrystallinecellulose in amounts representing 20 percent of the former and 80percent of the latter (by weight), and the substances are then mixed byany suitable means, such as by grinding with a mortar and pestle. Theformula may be encapsulated in a size of hard gelatin capsule suitableto contain the desired dose.

In a specific preparation, 540 mg. of a 20 percent formulation of(4-(2-fluorophenyl)phenyl)acetylene on microcrystalline cellulose wasfilled into a gelatin capsule, size 00. Each such capsule containedapproximately 108 mg. of (4-(2-fluorophenyl)phenyl)acetylene and 432 mg.of microcrystalline cellulose.

EXAMPLE 27

Cocoa butter (approximately 2.1 grams) is mixed with(4-(2-fluorophenyl)phenyl)acetylene, (approximately 0.1 gram) and theresulting mixture is melted with gentle heat and poured into a rectalsuppository mold of suitable size.

EXAMPLE 28

A tincture suitable for topical administration is prepared with thefollowing ingredients:

    ______________________________________                                        (4-(2-fluorophenyl)phenyl)-                                                   acetylene          1%        by weight                                        ethanol            50%       by volume                                        propylene glycol   20%       by volume                                        water              q.s.100%  by volume                                        ______________________________________                                    

The tincture is prepared by dissolving the(4-(2-fluorophenyl)-phenyl)acetylene with the ethanol, and thereafteradding the propylene glycol and water to the final volume.

EXAMPLES 29-52;

The compounds of the present invention were evaluated foranti-inflammatory activity by the ultraviolet-induced erythema blockingtest. The test procedures were a modification of the Winder method(Winder, C.V.; Wax, J.; Burr, V.; Been, M.; and Posiere, C.E.: A Studyof Pharmacological Influences on Ultraviolet Erythema in Guinea Pigs.Arch. Int. Pharmacodyn. 116: 261, 1958). Male albino guinea pigsweighing 240-300 gm. were used. The hair on the back was clipped andchemically depilated 15-18 hours before each experiment. The animalswere fasted overnight, and on the day of the experiment, were randomizedand placed in clear plastic partitioned holders 10 × 20 cm. wide and 15cm. high.

The compounds to be tested were suspended in 1% methyl cellulose inwater, utilizing a tissue homogenizer. The suspensions were administeredorally in a volume of 2.0 ml./kg. of body weight. Control animalsreceived an equal amount of the vehicle.

The source of ultraviolet light was a Hanovia lamp (Kromayer-Model 10).A notebook reinforcement ring was placed upon the lens of the lamp toprovide an area of contrast for grading purposes. The lens was thenplaced in contact with the skin of the guinea pig's back. Exposure timeto UV was for a period of 4 seconds. Beginning one hour after exposureand thereafter at half-hour intervals for another 11/2 hours, the degreeof resulting erythema was graded by an arbitrary scoring system basedupon the degree of contrast and redness formed. Anti-inflammatory agentsdelay the development of the erythema and have their greatest effect atthe initial grading periods. The scores were, therefore, weighted byfactors of 4, 3, 2, and 1 at the 1.0, 1.5, 2.0, and 2.5 hour scoringtimes, respectively. The erythema was graded as follows:

    ______________________________________                                        Erythema Scoring System                                                       Score   Appearance of Exposed Area                                            ______________________________________                                        0       No redness and no contrast                                            1       Slight redness with a faint reinforcement                                     outline                                                               2       Slight to moderate redness with a distinct                                    outline                                                               3       Marked redness with a distinct circular outline                       ______________________________________                                    

Total scores from each treatment group of four guinea pigs were comparedto the scores of the control group. The percent inhibition wascalculated as follows: ##EQU1## In the case of compounds showinginhibition, retesting was carried out at a plurality of doses to enablecalculation of an ED₅₀ for each such compound. ED₅₀ designates that dosewhich provides 50% inhibition. Calculation of the ED₅₀ was either by astandard linear regression method or by estimation from a dose-responsecurve of three or more points. The compounds so tested and their ED₅₀ swere as follows:

    ______________________________________                                        Compound                ED.sub.50 in mg./kg.                                  ______________________________________                                        4-biphenylylacetylene   0.9                                                   3-biphenylylacetylene   7                                                     (4-(2-fluorophenyl)phenyl)acetylene                                                                   0.05                                                  (4-(3-fluorophenyl)phenyl)acetylene                                                                   3                                                     (4-(2-chlorophenyl)phenyl)acetylene                                                                   0.8                                                   (4-(2,4-difluorophenyl)phenyl)acetylene                                                               4                                                     (4-(2,5-difluorophenyl)phenyl)acetylene                                                               4.4                                                   (2-methoxy-4-phenylphenyl)acetylene                                                                   39                                                    (2-methyl-4-n-butoxyphenyl)acetylene                                                                  35                                                    (3-chloro-4-cyclohexylphenyl)acetylene                                                                1.0                                                   (3-phenoxyphenyl)acetylene                                                                            13                                                    (2-methyl-4-phenoxyphenyl)acetylene                                                                   8                                                     (3-methyl-4-phenoxyphenyl)acetylene                                                                   10                                                    (3,5-dimethyl-4-phenoxyphenyl)acetylene                                                               11                                                    (4-(2-fluorophenoxy)phenyl)acetylene                                                                  16.5                                                  (3-(2-fluorophenoxy)phenyl)acetylene                                                                  12                                                    (4-(o-tolyl)phenyl)acetylene                                                                          0.9                                                   (4-(2,6-difluorophenyl)phenyl)acetylene                                                               12.0                                                  (2-methyl-4-phenylphenyl)acetylene                                                                    20.0                                                  (3-chloro-4-phenylphenyl)acetylene                                                                    0.033                                                 (3-fluoro-4-phenylphenyl)acetylene                                                                    0.5                                                   (4-fluoro-3-(2-fluorophenyl)phenyl)-                                          acetylene               23                                                    (3-methyl-4-phenylphenyl)acetylene                                                                    0.09                                                  (3-methoxy-4-phenylphenyl)acetylene                                                                   0.6                                                   ______________________________________                                    

EXAMPLE 53

(4-(2-Fluorophenyl)phenyl)acetylene was also evaluated foranti-inflammatory effect when applied topically. The test procedureswere the same as those reported in Examples 29-52 except for threedifferences: the compound was applied topically in an alcohol solutionimmediately after exposure to the ultraviolet; scores were not weighted;and results were recorded only as percent inhibition. The results wereas follows:

    ______________________________________                                        Erythemic Scores                                                              Time after U.V. Exposure                                                      Total                                                                         Amount  1       1.5     2     2.5   Total %                                   Applied Hr.     Hr.     Hr.   Hr.   Score Inhibition                          ______________________________________                                        Control 17      20      20    21    78    --                                  (alcohol solution)                                                            100 μg                                                                             0        1       4     8    13    83                                   10 μg                                                                             5       10      14    17    46    41                                   1 μg                                                                              6       13      18    19    56    28                                  ______________________________________                                    

EXAMPLE 54

(4-(2-Flourophenyl)phenyl)acetylene was evaluated again by theprocedures of Examples 29-52, except that the compound was administered8 or 22 hours prior to exposure to ultraviolet light. The dose wasuniformly 0.5 mg./kg. Readings were made at half-hour intervalsbeginning at one-half hour after exposure and ending at three andone-half hours after exposure. Scores were not weighted, and resultswere recorded only as percent inhibition. The results were as reportedbelow.

    __________________________________________________________________________               Scores at Respective Hours after                                              Exposure to Ultraviolet                                                                              Total                                                                             % Erythema                              Treatment  0.5                                                                              1.0 1.5 2.0 2.5 3.0 Score                                                                             Inhibition                              __________________________________________________________________________    Control    8  16  18  20  21  21  104 --                                      0.5 mg./kg. of                                                                (4-(2-fluoro-                                                                 phenyl)phenyl)-                                                               acetylene 8 hours                                                             prior to ultra-                                                               violet exposure                                                                          0  0   3   6   6   15  30  71                                      Control    7  18  19  21  21  21  107 --                                      0.5 mg./kg. of                                                                (4-(2-fluoro-                                                                 phenyl)phenyl)-                                                               acetylene 22 hours                                                            prior to ultra-                                                               violet exposure                                                                          3  4   8   14  17  17  63  41                                      __________________________________________________________________________

EXAMPLE 55

(4-(2-Fluorophenyl)phenyl)acetylene was also evaluated for the controlof inflammation in dogs. The testing procedures were the same asreported in the preceding examples except for these differences: a10-second exposure time was used; non-pigmented abdominal skin was used;and the observed erythema was graded every half hour over a three-hourperiod with no weighting of scores. A placebo control was run with thesame test dogs on the day prior to treatment. The resuls were asfollows:

    ______________________________________                                                              Total                                                                         Erythemic   % Erythema                                  Dog No.   Dose        Score       Inhibition                                  ______________________________________                                        05        Control     14          --                                          05        10 mg/kg     0          100                                         04        Control     15          --                                          04        5 mg/kg      0          100                                         05        Control     14          --                                          05        1 mg/kg      4           71                                         ______________________________________                                    

EXAMPLES 56-58

Representative compounds of the present invention were evaluated foranti-inflammatory activity in rats using an adjuvant-induced arthritistest.

The test method was that of Winter et al., 9 Arthritis and Rheumatism394 (1966). Male, specific pathogen-free albino rats, weighingapproximately 200 g., were used. The arthritic syndrome was induced byinjection of 0.05 ml. of a fine suspension of dead Mycobacteriumtuberculosum bacilli in mineral oil (concentration 5 mg./ml.) through aneedle into the plantar surface of the right hind foot. The tuberclebacilli were derived from human strains PN, DT and C which were grownfor eight weeks, killed by steam and dried in a vacuum oven.

One day before injection of adjuvant and daily thereafter for thirteendays, a suspension of test compound in 1% sodium carboxymethylcellulosein water was administered orally to rats. In control rats an edematouspaw was induced which reached its maximum size between about day 7 andday 10.

A measurement of the edema of the tested rats was made by dipping therat's foot into a well, displacing mercury. The pressure from themercury was transferred into electrical output by a Digital VolumetricMeasurement System, using a transducer. The paw volume was measured onthe day adjuvant was administered (day two) and again on day seven andday fourteen of the test. The initial (day two) volume was subtractedfrom the volumes on the seventh and on the fourteenth days, and thepercent volume increases were calculated. Percent inhibition wascalculated by comparing percent increases of treated and control groups.All readings and measurements were done in blind studies. The activitiesof the compounds measured by this test are shown below.

    ______________________________________                                                         Percent Inhibition                                                            of Volume Increase                                           ______________________________________                                        Compound       Dose    Day 7      Day 14                                      ______________________________________                                        4-biphenylylacetylene                                                                        25      29         37                                                                 37         23                                                         3       14          7                                                         1        0          0                                                         0.3     15          0                                          (2-(2,5-difluoro-                                                             phenyl)phenyl)-                                                               acetylene      25      38         15                                          (3-chloro-4-phenyl-                                                           phenyl)acetylene                                                                             3       30         45                                                         1       34         41                                                         0.3     56         50                                                         0.1     21         36                                          ______________________________________                                    

EXAMPLE 59

(4-(2-Fluorophenyl)phenyl)acetylene was evaluated repeatedly by theprocedures reported in Examples 56-58. In two sets of representativetests, the compounds performed as reported in the following table:

    ______________________________________                                                  Percent Inhibition of                                                         Volume Increase                                                     ______________________________________                                        Dose        Day 7         Day 14                                              ______________________________________                                        10          30            5                                                   3           35            21                                                  1           27            14                                                  10          23            0                                                   3           29            0                                                   1           22            0                                                   ______________________________________                                    

EXAMPLES 60-80

Representative compounds were also evaluated for anti-inflammatoryactivity in the test method described by C. A. Winter at 111 Proc. Soc.Exp. Biol. Med., 544 (1962). In this method, inflammation is created byinjecting carrageenin into the hind paw of rats. Test compounds areadministered prior to injection to determine percent inhibition of thesubsequent inflammation, in comparison with control animals. The resultswere as reported below.

    ______________________________________                                                          Dose in                                                     Compound          mg./kg.    % Inhibition                                     ______________________________________                                        (2-methyl-4-phenoxy-                                                          phenyl)acetylene  25         33                                               (3-phenoxyphenyl)-                                                            acetylene         10         7                                                (3-methyl-4-phenoxy-                                                          phenyl)acetylene  10         16                                               (3,5-dimethyl-4-phenoxy-                                                      phenyl)acetylene  50         29                                               4-biphenylylacetylene                                                                           50         41                                                                 20         45                                                                 10         42                                                                 5          37                                                                 10         56                                                                 3          36                                                                 1          0                                                                  5          26                                                                 1          0                                                                  0.5        0                                                                  10         51                                                                 3          41                                                                 1          45                                               (4-(3-fluorophenyl)-                                                          phenyl)acetylene  10         17                                               (4-(2,4-difluoro-                                                             phenyl)phenyl)-                                                               acetylene         25         31                                               (4-(2,5-difluorophenyl)-                                                      phenyl)acetylene  25         43                                               (2-methoxy-4-phenyl-                                                          phenyl)acetylene  50         51                                                                 10         7                                                                  1          25                                               (2-methyl-4-n-butoxy-                                                         phenyl)acetylene  25         9                                                (4-(2-fluorophenyl)-                                                          phenyl)acetylene  25         65                                                                 10         51                                                                 2.5        35                                                                 1          29                                                                 3          57                                                                 1          31                                                                 0.3        21                                                                 50         57                                                                 15         56                                                                 5          43                                                                 10         52                                                                 3          35                                                                 1          43                                                                 5          36                                                                 1.5        29                                                                 0.5        6                                                                  10         30                                                                 3          32                                                                 1          0                                                                  5          35                                                                 1          29                                                                 0.5        6                                                (4-(2-chlorophenyl)-                                                          phenyl)acetylene  50         52                                               3-biphenylylacetylene                                                                           50         32                                               (3-chloro-4-phenyl-                                                           phenyl)acetylene  10         62                                                                 3          41                                                                 0.3        23                                               (3-methyl-4-phenyl-                                                           phenyl)acetylene  50         66                                                                 30         56                                                                 10         56                                                                 3          37                                               (4-(o-tolyl)phenyl)-                                                          acetylene         50         48                                                                 30         53                                                                 10         6                                                                  3          16                                               (3-(2-fluorophenoxy)-                                                         phenyl)acetylene  50         32                                               (4-(2-fluorophenoxy)-                                                         phenyl)acetylene  30         68                                                                 10         45                                                                 10         44                                                                 3          28                                               (4-fluoro-3-(2-fluoro-                                                        phenyl)phenyl)acetylene                                                                         50         45                                                                 30         43                                                                 10         23                                                                 3          13                                               (4-(2,6-difluorophenyl)-                                                      phenyl)acetylene  50         49                                                                 30         37                                                                 10         34                                                                 3          7                                                (3-fluoro-4-phenyl-                                                           phenyl)acetylene  50         54                                                                 50         77                                               ______________________________________                                    

EXAMPLES 81-82

Each of 4-biphenylylacetylene and (4-(2-fluorophenyl)phenyl)acetylenewas evaluated again in the carrageenin induced test method reported inExamples 60-80. However, in these tests, the compound was administeredabout 20 hours prior to the test procedures. The results were asfollows:

    ______________________________________                                                                 %                                                                    Dose     Inhibition                                           ______________________________________                                        4-biphenylylacetylene                                                                           10         44                                                                 10         28                                               (4-(2-fluorophenyl)-                                                          phenyl)acetylene  10         42                                                                 10         60                                               ______________________________________                                    

EXAMPLE 83

(4-(2-Fluorophenyl)phenyl)acetylene was evaluated for antipyretic effectin rats. Fever was induced by subcutaneous injection of yeast, atechnique reported at 54 J. Pharm. Exp. Ther. 346 (1935). A total of 24rats was employed, divided into 6 treatment groups. One group was anormal control, without even the yeast injection. A second group servedas a yeast control, receiving yeast injection but none of the testcompound. All of the remaining groups received the test compound, in thefollowing pattern:

no yeast + 100 mg./kg. of compound

yeast + 100 mg./kg. of compound

yeast + 50 mg./kg. of compound

yeast 30 10 mg./kg. of compound

The procedure was that yeast was administered to all rats at the sametime, and temperatures were ascertained two hours later, at which timethe test compound was administered to those groups assigned to receiveit. Temperatures of all animals were also recorded thereafter at 1.0,1.5, 2.0, 2.5, and 3.0 hours following administration of the testcompound.

Resulting data was analyzed statistically, showing the following:

1. Comparing all rats receiving yeast with all rats not receiving yeast,the former exhibited mean temperatures above the mean temperatures ofthe latter, and the differences were statistically significant. Thisconfirms the validity of the fever-inducing technique. 2. In ratsreceiving no yeast injection, some lowering of temperature occurredafter administration of (4-(2-fluorophenyl)phenyl)acetylene, but thechange was not statistically significant when compared with differencesobserved in the normal control and yeast control groups. 3. Temperaturesof all rats receiving both yeast and (4-(2-fluorophenyl)phenyl)acetylenewere uniformly lower following administration of the test compound forall three dose levels of (4-(2-fluorophenyl)phenyl)acetylene and at allreading times. At the 1.5 hour reading for each of 50 mg./kg. and 100mg./kg. and at the 1.0 hour reading for all dose levels, the differenceswere not statistically significant. At all other doses, the differenceswere statistically significant, indicating that(4-(2-fluorophenyl)phenyl)acetylene exhibited antipyretic action.

EXAMPLES 84-102

Representative compounds were also evaluated for analgesic activity. Theevaluation was conducted by using acetic acid-induced writhing in miceas the pain model. Clinically effective analgesis are effective whentested in this model: see Koster et al., "Acetic Acid for AnalgesicScreening," 18 fed. Proc. 412 (1959).

In a method similar to that reported by Koster et al., standard strainalbino male mice weighing 20-22 grams were fasted overnight. Therespective compound or vehicle (as control) was administered by gastriclavage (p.o.). Each compound was administered in an aqueous suspensionof 1% methylcellulose in water. Control mice received comparable amountsof the vehicle only. At 30, 90, and 180 minutes after administration,writhing was induced by the intraperitoneal administration of 55 mg./kg.of acetic acid (0.55%). Each treatment group consisted of 5 mice andseparate groups were examined at each observation time. The total numberof writhes for the treatment group were counted in a 10-minuteobservation period starting 5 minutes after the acetic acidadministration. The treatment totals were compared to controls and apercent inhibition calculated as follows: ##EQU2## If a compoundinhibited writhing at 100 mg./kg., lower doses were generally examined.An ED₅₀, which represented the dose that would reduce the writhingfrequency by 50%, was estimated from a dose-response curve of three ormore points. A dose range was reported if only two points were availablefor the dose response curve and they bracketed the 50% level. If datawas available at 100 mg./kg. only, then the estimated ED₅₀ was reportedsimply as less than 100 (<100).

The results were as reported below:

    ______________________________________                                                                Estimated ED.sub.50,                                  Compound                mg./kg.                                               ______________________________________                                        4-biphenylylacetylene   50                                                    3-biphenylylacetylene   50-100                                                (4-(o-tolyl)phenyl)acetylene                                                                          35                                                    (2-methyl-4-phenylphenyl)acetylene                                                                    60                                                    (3-methyl-4-phenylphenyl)acetylene                                                                    50                                                    (4-(2-chlorophenyl)phenyl)acetylene                                                                   20-100                                                (3-chloro-4-cyclohexylphenyl)acetylene                                                                <100                                                  (3-chloro-4-phenylphenyl)acetylene                                                                    30                                                    (4-(2-fluorophenyl)phenyl)acetylene                                                                   20                                                    (4-(3-fluorophenyl)phenyl)acetylene                                                                   35                                                    (4-(2,4-difluorophenyl)phenyl)acetylene                                                               4                                                     (4-(2,5-difluorophenyl)phenyl)acetylene                                                               10                                                    (4-(2,6-difluorophenyl)phenyl)acetylene                                                               <100                                                  (3-fluoro-4-phenylphenyl)acetylene                                                                    10                                                    (4-(2-fluorophenoxy)phenyl)acetylene                                                                  <100                                                  (3-phenoxyphenyl)acetylene                                                                            <100                                                  (2-methyl-4-phenoxyphenyl)acetylene                                                                   <100                                                  (3-methyl-4-phenoxyphenyl)acetylene                                                                   <100                                                  (3,5-dimethyl-4-phenoxyphenyl)acetylene                                                               <100                                                  ______________________________________                                    

The compounds to be employed as starting materials in the firstsynthetic route: ##STR2## are themselves prepared in known procedures.Several such procedures are as follows: ##STR3## Similarly, thecompounds to be employed as the starting materials in the secondsynthetic route are also prepared in known procedures: ##STR4##Representative preparations follow.

A solution of 200 g. of 2-fluorobiphenyl in 1500 ml. of CS₂ was cooledto 0°-5° C. and treated with 200 g. of aluminum chloride over 140minutes and then with 113 g. of acetyl chloride over 165 minutes. Themixture was allowed to warm to room temperature and stirred overnight.The reaction mixture was then poured carefully into ice and hydrochloricacid, and organic material was extracted with a mixture of diethyl etherand ethyl acetate. The organic extract was washed with water, 10% sodiumhydroxide, and water, and dried over sodium sulfate. Evaporation of thesolvents in vacuo and recrystallization of the solid residue from hexanegave (4'-(2-fluorophenyl)acetophenone. This was recrystallized fromhexane to give two crops Crop one, 173 g., m.p. 84.5-86.5° C.

Analysis, Calc. for C₁₄ H₁₁ FO: C, 78.49; H, 5.18; F, 8.87, Found: C,77.23; H, 4.75; F, 10.00. Crop two, 51.1 g., m.p. 85°-87° C.

Analysis, Calc. for C₁₄ H₁₁ FO: C, 78:49; H, 5.18; F, 8.87, Found: C,78.40; H, 5.35; F, 8.89.

In another preparation, a Grignard reagent was prepared from 100 g. of3-bromobiphenyl and 10 g. of Mg in diethyl ether. To this solution wasadded 40 g. of CdCl₂ .sup..2 H₂ O at 4° C. during one hour. The reactionmixture was then refluxed for an hour, cooled, and a diethyl ethersolution of 32 g. of acetyl chloride added at 12° C. over a period of 30minutes. The reaction mixture was refluxed for 30 minutes and allowed tocool to room temperature and stir overnight. Additional diethyl etherwas added and the reaction mixture was refluxed for an hour. Aftercooling, 100 ml. of ammonium chloride solution was added, followed by100 ml. of water. The reaction mixture was poured onto ice and thediethyl ether layer separated. The diethyl ether extract was washed withwater (until the washes were neutral), dried over sodium sulfate, andevaporated to dryness. The residue was distilled to yield 29.3 g. of3'-phenylaceacetophenone, b.p. 120° C./0.3 mm., after low boilingearlier fractions had been separated.

Analysis, Calc. for C₁₄ H₁₂ O: C, 85.68; H, 6.16; O, 8.15, Found: C,85.62; H, 6.33; O, 8.18.

In another preparation, a Grignard reagent was prepared by allowing 5.3g. of Mg to react with 54 g. of 2-fluoro-4-bromobiphenyl intetrahydrofuran. A solution of 9.7 g. of acetaldehyde in 100 ml. oftetrahydrofuran was added dropwise to the cooled Grignard solution.After addition was complete another 125 ml. of tetrahydrofuran was addedand the solution was stirred overnight at room temperature.

After cooling, 165 ml. of saturated ammonium chloride solution wereadded dropwise followed by 100 ml. of water. After warming to roomtemperature, the reaction mixture was poured onto ice. The product wasextracted into ether and the ether extract was washed three times withwater, dried over sodium sulfate, and the ether was evaporated in vacuo.The solid residue was crystallized from hexane to yield 26.3 g. ofα-methyl-3-fluoro-4phenylbenzyl alcohol, m.p. 84°-86° C.

Analysis, Calc. for C₁₄ H₁₃ FO: C, 77.76; H, 6.06, Found C, 77.52; H,6.33.

A solution of 12 g. of CrO₃ in 42 ml. of 35% sulfuric acid was addeddropwise to a well stirred, cooled solution of 28.6 g. ofα-methyl-3-chloro-4-phenylbenzyl alcohol in 36 ml. of acetone. A largevolume of additional acetone was then added and the aqueous layerseparated. This was separated and washed with additional acetone, andthe combined acetone solutions were dried over sodium sulfate andevaporated. The residual liquid was distilled to yield 26.3 g. of3'-chloro-4'-phenylacetophenone b.p. 132°-141° C./ 0.09 mm.

Analysis, Calc. for C₁₄ H₁₁ ClO: C, 72.89; H, 4.81, Found: C, 72.63; H,4.85.

We claim:
 1. A method of treating inflammation in a warm-blooded animalwhich comprises administering to the animal an effective amount of anactive agent which is a compound of the formula: ##SPC4##wherein qrepresents 0, 1, or 2; each R¹ independently represents chloro orfluoro; and R² represents
 1. phenyl; and
 2. substituted phenyl of theformula ##SPC5##wherein each R³ independently represents chloro orfluoro and n represents 1 or 2; provided that q must be other than 0when R² is phenyl.
 2. A method of treating inflammation, fever or painin a warm-blooded animal which comprises administering to the animal aneffective amount of an active agent which is a compound selected fromthe group consisting of (4-(2-fluorophenyl)phenyl)acetylene,(3-fluoro-4-phenylphenyl)acetylene, and(4-(2,4-difluorophenyl)phenyl)acetylene.
 3. The method of claim 1wherein the active agent is (4-(2-fluorophenyl)phenyl)acetylene.
 4. Themethod of claim 2 wherein the active agent is(3-fluoro-4-phenylphenyl)acetylene.
 5. The method of claim 2 wherein theactive agent is (4-(2,4-diflurophenyl)phenyl)acetylene.
 6. Apharmaceutical preparation in a dosage unit form adapted for oraladministration to obtain an anti-inflammatory, anti-pyretic, oranalgesic effect, comprising, per dosage unit, an effective non-toxicamount within the range from about 1 to about 1000 milligrams of anactive agent, and a pharmaceutical diluent, said active agent beingeither (4-(2-fluorophenyl)phenyl)acetylene or(3-fluoro-4-phenylphenyl)acetylene.
 7. The preparation of claim 6wherein the active agent is (4-(2fluorophenyl)phenyl)acetylene.
 8. Thepreparation of claim 6, wherein the active agent is(3-fluoro-4-phenylphenyl)acetylene.